The present invention relates to a method of treating estrogen deficiency in the central nervous system without influencing other organs or systems by administration of a pharmaceutical preparation of selected steroids and to the pharmaceutical composition used in that method.
These steroids are characterized by a selective neurotropic, estrogen-like transcription action in contrast to the systematically acting natural and synthetic estrogens, including 17.alpha.-estradiol. These steroids are compounds of the general formula I: ##STR1##
wherein R.sub.1 represents a hydrogen atom, a hydroxy group or an alkoxy group having 1 to 5 carbon atoms; R.sub.2 represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an acyl group having 1 to 5 carbon atoms or a group of the formula SO.sub.2 NR.sub.10 R.sub.11, wherein R.sub.10 and R.sub.11 represent, independently of each other, a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or together with nitrogen, a pyrrolidino group, a piperidino group or a morpholino group; R.sub.3 represents a hydrogen atom or a hydroxy group; R.sub.4 represents a hydrogen atom, a hydroxy group or an alkyl group with 1 to 5 carbon atoms; R.sub.5 and R.sub.6 each represent, independently of each other, a hydrogen atom or a halogen atom; R.sub.7 represents hydrogen or a methyl group; R.sub.8a represents a hydrogen and R.sub.8b represents a hydroxy group or R.sub.8a represents a hydroxy group and R.sub.8b represents a hydrogen or both together represent an oxo group or a group of formula CR.sub.12 R.sub.13, in which R.sub.12 and R.sub.13 each represent, independently of each other, a hydrogen atom or a halogen atom; R.sub.9 represent a methyl or an ethyl group; Z either represents a double bond or a substituted or unsubstituted cyclopropane ring; and &gt;CR.sub.5 R.sub.6 is an a group or a .beta. group and R.sub.7 is a .beta. group when &gt;CR.sub.5 R.sub.6 is an .alpha. group and vice versa.
An abrupt or gradual decrease of the estrogen concentrations in organisms can occur both in women and in men in various physiological conditions (increasing age, menopause) and pathological conditions (gonadectomy, use of GnRH analogs in supplemental cancer therapy). Troublesome thermoregulation in the form of hot flashes, osteoporosis and an increased predisposition to heart and circulatory illness are part of the best known clinical symptoms of estrogen deficiency (A. Netter, "The menopause", in C. Thibault, M. C. Levasseur, R. H. F. Hunter (eds.), Reproduction in Mammals and Man, Ellipses, Paris, 1993, pp. 627 to 643). The latest clinical studies (A. W. van den Beld, et al, "The Role of Estrogens in Physical and Psycho-social Well-being in Elderly Men", The Aging Male 1 (Suppl. 1), 54, 1998) definitely prove the connection between decreased serum estrogen levels and increasing aging in man. Because of that the presence and patho-physiological relevance of an "estrogen deficiency syndrome" in aging men is underscored.
The brain is a very important target organ for estrogen action. Estrogens have a decisive physiological effect on numerous neurobiological processes. Their action may be classified generally into two broad classes, organizing action and activating action (B. S. McEwen, et al, "Steroid Hormones as Mediators of Neural Plasticity", J. Steroid Biochem. Mol. Biol., 39, 223 to 232, 1991).
The first group relate primarily to the gender-specific organization of neural substrates during early ontogenesis.
The second group include specific changes in the function of neural regulatory cycles that are influenced by estrogen concentrations, which result from physiological secretion of the gonads after gender maturation. The activating effect of estrogens in the central nervous system has been reported in the following physiological processes, among others:
Gender-specific regulation of gonadotropin secretion (G. Fink, "Gonadotropin Secretion and its Control", in E. Knobil and J. D. Neil(eds.), The Physiology of Reproduction, Raven Press, New York, 1348 to 1376, 1998);
Control of Sexual Behavior (M. J. Baum, et al, "Hormonal Basis of Proceptivity and Receptivity in Female Primates", Arch. Sex. Behav. 6, 173 to 192, 1977);
Regulation of Neuroendocrine Reactions during Stress (V. Viau and M. J. Meaney, "Variations in Hypothalamic-pituitary-adrenal Response to Stress during the Estrous Cycle in the Rat", Endrocrinology 129, 2503 to 2511, 1991);
Learning and Retention of Behavioral Patterns in Adaptive Relevance (M. F. O'Neal, et al, "Estrogen Affects Performance of Ovariectomized Rats in a Two-choice Water-escape Working Memory Task", Psychoneuroendorcrinology 21, 51 to 65, 1996);
Maintenance of Reactivity of Neurochemical Mechanisms that are Indispensible for Guaranteeing Alterness and Adequate Information Processing (G. Fink, et al, "Estrogen Control of Central Neurotransmission: Effects on Mood, Mental State and Memory", Cell. Mol. Neurobiol. 16, 325 to 344, 1996);
Brain structure with Decisive Roles for Cognitive Performance and Emotional States (C. S. Wooley, B. S. McEwen, "Estradiol Mediates Fluctuations in Hippocampal Synapse Density During the Estrous Cycle in the Adult Rat", J. Neurosci. 12, 2549 to 2554, 1992);
The great neurotropic potential of estrogens finds its expression in their ability:
to induce expression of a series of central nervous system specific genes, whose products are of critical significance for the survival of nerve cells (R. C. Miranda, F. Sohrabji, C. D. Toran-Allerand, "Presumptive Estrogen Target Neurons Express mRNA for both the Neurotrophins and Neurotrophin Receptors: A Basis for Potential Development Interactions of Estrogen with the Neurotrophins", Mol. Cell. Neurosci. 4, 510 to 525, 1993); PA1 to guarantee the variety and quality of the signal transmission in the central nervous system (V. N. Luine, "Estradiol Increases Choline Acetyltransferase Activity in Specific Basal Forebrain Nuclei and Projection Areas of Female Rates", Exp. Neurol. 89, 489 to 490, 1985); (N. Weiland, "Glutamic Acid Decarboxylase Messenger Ribonucleic Acid is Regulated by Estradiol and Progesterone in the Hippocampus", Endocrinology 131, 2697 to 2702, 1992); (R. Bosse, T. DiPaolo, "The Modulation of Brain Dopamine and GABA.sub.A Receptors by Estradiol: A Clue for CNS Changes occuring at Menopause", Cell Mol. Neurobiol. 16, 199 to 212, 1996); and PA1 to increase the resistance of nerve cells against pathological action (Y. Goodman, et al, "Estrogens Attenuate and Corticosterone Exacerbates Excitotoxicity, Oxidative Injury, and Amyloid b-peptide Toxicity in Hippocampal Neurons", J. Neurochem. 66, 1836 to 1844, 1996). PA1 stimulation of biosynthesis of natural neuronal growth factors; PA1 stimulation of activity of acetyl choline synthesizing enzymes or uptake of substrates of acetyl choline synthesis; PA1 direct cytoprotection by increasing resistance of nervecells from the withdrawal of nutrient substrates or growth factors; and PA1 reduction of the sensitivity of nerve cells to free radicals and reactive oxygen species, which are released because of a traumatic or neurotoxic reaction. PA1 had a selective influence on the transcription estrogen-dependent genes in CNS and cause changes of suitable physiological parameters; PA1 had CNS-specific transcription effects in the dosages used with no biological effects in tissues of the reproductive system; PA1 had CNS specific transcription effects at those dosages at which neither 17.beta.-estradiol nor 17.alpha.-estradiol had any action; and PA1 the transcription estrogen-dependent gene in the CNS is not influenced by the action of secondarily formed 17.beta.-estradiol. PA1 15.beta.H,3'H-cycloprop[14,15]-estra-1,3,5(10),8-tetraen-3,17.alpha.-diol, PA1 15.beta.H,3'H-cycloprop[14,15]-18.alpha.-homo-estra-1,3,5(10),8-tetraen-3,1 7.alpha.-diol, PA1 17.alpha.-hydroxy-15.beta.H,3'H-cycloprop[14,15]-estra-1,3,5(10),8-tetraen- 3-yl-pentanoate, PA1 17-methylene-15.beta.H,3'H-cycloprop[14,15]-estra-1,3,5(10),8-tetraen-3-ol, PA1 15.beta.H,3'H-3',3'-difluoro-cycloprop[14,15]-estra-1,3,5(10),8-tetraen-3,1 7.alpha.-diol, PA1 17-methylene-15.beta.H,3'H-cycloprop[14,15]-estra-1,3,5(10),8-tetraen-3-yl- sulfamate, PA1 17-difluoromethylen-15.beta.H,3'H-cycloprop[14,15]-estra-1,3,5(10),8-tetrae n-3-ol, PA1 3-methoxy-15.beta.-methyl-3'H-cycloprop[14,15]-estra-1,3,5(10),8-tetraen-3- ol, PA1 15.alpha.-methyl-3'H-cycloprop[14,15]-estra-1,3,5(10),8-tetraen-3,17.alpha. -diol, PA1 17-difluoromethylen-15.beta.H,3'H-cycloprop[14,15]-estra-1,3,5(10),8-tetrae n-3-yl-(tetramethylenimino)sulfonate, and PA1 17-methylene-3'H-cycloprop[8,9]-15.beta.H,3'H-cycloprop[14,15]-estra-1,3,5( 10)-trien-3-ol. PA1 tablets or pills for daily oral administration including from 0.1 to 2 mg of the effective ingredient of the invention; PA1 ampoules for daily subcutaneous injection including from 0.1 to 2 mg of the effective ingredient of the invention; PA1 plasters for transdermal release daily of from 0.05 to 2 mg of the effective ingredient of the invention; PA1 gels and creams for transdermal release daily of 0.05 to 2 mg of the effective ingredient of the invention; and PA1 buccal administration systems for daily release of 0.1 to 1 mg of the effective ingredient of the invention.
Clinical findings implicate estrogen deficiency as a causal factor in Morbus Alzheimer's pathogenicity, which maintains the clinical manifestation or progression of this disease, and point to the possiblity of estrogen replacement (V. W. Henderson, et al, "Estrogen Replacement Therapy in Older Women: Comparisons Between Alzheimer's Disease Cases and Controls", Arch. Neurol. 51, 896 to 900, 1994); (A. Paganini-Hill, V. W. Henderson,"Estrogen Deficiency and Risk of Alzheimer's Disease", Am. J. Epidemiol. 140, 256 to 261, 1994). A series of neuropeptides, whose gene transcription is influenced by physiological estrogen amounts (e.g. oxytocin and arginine vasopressin) play an important role in the control of emotional behavior components (R. A. Adan, J. P. Burbach, "Regulation of Vasopressin and Oxytocin Gene Expression by Estrogen and Thyroid Hormone", Progr. Brain Res. 92, 127 to 136, 1992).
Reports in the literature point out that estrogen deficiency is accompanied by a definite weakening of the organism's ability to eliminate reactive oxygen species and free radicals (E. Niki, M. Nakano, "Estrogens as Antioxidants", Methods Enzymol. 186, 330 to 333, 1990); (M. Lacort, et al,"Protective Effects of Estrogens and Catecholestrogens against Peroxidative Membrane Damage In Vitro", Lipids 30, 141 to 146, 1995). The excess of free radicals is implicated in mechanisms of cellular damage in many organs and systems and is connected with pathogenesis of neurodegenerative illnesses (C. D. Smith, et al, "Excess rain Protein Oxidation and Enzyme Dysfunction in Normal gain and in Alzheimer's Disease", Proc. Natl. Acad. Sci. USA 88, 10540 to 10543, 1991); (T. G. Hastings, M. J. Zigmond, "Neurodegenerate Disease and Oxidative Stress: Insights from an Animal Model of Parkinsonism" in G. Fiskum (ed), Neurodegenerate Diseases, Plenum Press, New York, 37 to 46, 1996). Also estrogen replacement assumes a role in maintaining and increasing endogenous antioxidative capacity (C. Behl, et al, "17.beta.-Estradiol Protects Neurons from Oxidative Stress-induced Cell Death In Vitro", Biochem. Biophys. Res. Commun. 216, 473 to 482, 1995).
At the present time estrogen replacement occurs with natural and synthetic estrogens, whose action occurs in all estrogen-receptor-containing organs and systems, i.e. practically the entire body. However since these estrogens already cause great cell profileration in tissues of the female genital tract (endometrium) and breast gland epithelium, which subsequently develops into a carcinogenic differentiation, their use for therapy of symptoms of an estrogen deficiency is limited by several counter indications (B. A. Berstein, R. K. Ross, B. E. Henderson, "Relationship of Hormone Use to Cancer Risk", J. Natl. Cancer Inst. Monograph 12, 137 to 147, 1992).
The profilerative effects of estrogens involve direct risk factors for causing a benign prostate hyperplasia and/or gynecomastia in man(C. Knabbe, "Endocrine Therapy of Prostate Disease", in B. Allolio, H. M. Schulte (eds.), Practical Endocrinology, Urban & Schwarzenberg, Munchen, 645 to 651, 1996). For this reason estrogen replacement in man, despite these known indications, has never been seriously considered.
The use of natural and synthetic estrogens with systematic action, i.e. in all organs and systems of the body, to treat neurodegenerative illnesses is claimed in the following patents: U.S. Pat. No. 4,897,389, U.S. Pat. No. 5,554,601, International Patent Documents WO 95/12402 and WO 97/03661 and German Patent Document DE 43 38 314 C1.
U.S. Pat. No. 4,897,389 protects the use of estradiol, estrone and estriol, alone or in combination with gonadotropins, androgens, anabolic androgens or human growth hormones, for treatment of senile dementia, Morbus Parkinsons, cerebral atrophy, Morbus Alzheimers, cerebellar atrophy, senile or essential tremor.
U.S. Pat. No. 5,554,601 and WO 95/12402 protects the use of estrogen substances which have slight "sexual activity" for protection of nerve cells from progressive damage and cell death, and for treatment of neurodegenerative diseases. The estrogen, 17.alpha.-estradiol, is mentioned as an example of a substance with slight "sexual activity" and neuroprotective action.
WO 97/03661 protects the use of non-estrogenic substances, which have at least two ring structures, in which at least one is a terminal phenolic ring, and whose molecular weight is less than 1000 Daltons, to guarantee neuroprotection.
German Patent Document DE 43 38 314 C1 describes steroids with a phenolic A ring structure, whose radical trapping and antioxidative properties, do not depend on the extent of their estrogen-similar activity. These compounds can be used for prophylaxis and therapy of radical-mediated cell damage.
In all these patents the therapeutic and neuroprotective efficiency of the obtained substances depends on one or more of the following end effects:
However, none of these patents describes a steroid with selective estrogen-similar neurotropic transcription effects; i.e., those, which in a dosage in vivo, which produces no significant biological action in reproductive systems, influences the transcription of estrogen-dependent genes in the central nervous system in an estrogen-similar manner. It should be particularly emphasized that the action escribed in U.S. Pat. No. 5,554,601 and WO 95/12402 of 17.alpha.-estradiol, a substance which has a reduced estrogenicity in the genital tract (J. H. Clark, et al, "Effects of Estradiol 17.alpha. on Nuclear Occupancy of the Estrogen Receptor, Stimulation of Nuclear Type II Sites, and Uterine Growth", J. Steroid. Biochem. 16, 323 to 328, 1982), relates only to the protection of cultivated nerve cells prior to cell death induced by withdrawal of nutrient media, in which the relative potency of 17.alpha.-estradiol was not compared or evaluated together with 17.beta.-estradiol. Moreover one concludes that a suggestion of selective neurotropic action of 17.alpha.-estradiol or its derivatives is absent from the current experimental and patent literature, while 17.beta.-estradiol is known to have no central nervous system selectivity and thus is classified as an estrogen with systemic action. The patent WO 97/03661 and DE 43 38 314 C1 interprets the cytoprotective action of estrogens as a consequence of the radical trapping properties of its terminal phenolic A-ring. A dissociated neurotropic action of 17.alpha.-estradiol, which is based on influencing the transcription of the estrogen-sensitive genes, was neither attempted in the work disclosed in the patents nor reported in the literature.